This invention relates to novel compositions of matter which are ion-complexing agents, to the use of the agents to detect cations, and to complexes of the compounds with cations.
Lithium is present in the blood of patients undergoing therapy for manic depression. It is important to maintain effective serum lithium levels for optimum treatment and at the same time the likelihood of lithium toxicity increases with increased serum lithium levels. Therefore, it is important to carefully monitor blood lithium levels in these patients.
Clinical chemistry analyzers can utilize ion-selective electrodes (ISE's) for direct potentiometric determination of levels of cations such as those of sodium and potassium in blood serum, plasma and urine. Clinical analysis of lithium in these human bodily fluids, however, requires an ISE with high selectivity for lithium relative to sodium and potassium which are likely to be present with lithium. Suitable ionophores have not been available with the required selectivity of less than 1% interference by sodium (Metzger, et al., Anal. Chem. 1987, 59, 1600-1603). In addition, a microelectrode selective for lithium would also have important applications in biomedical research for detecting local ion concentrations in tissues such as nerve fibers.
Lithium ISE's based on crown compounds and acyclic compounds are known (Moody et al., Chemical Sensors, Edmonds, Ed., Chapman & Hall, New York (1988) Chpt. 3). Derivatives of 14-crown-4 ethers selective for Li.sup.+ have been described (Kimura et al., Anal. Chem. 1987 59, 2331-2334; Xie et al., Analyst 1987 112, 61-64). Lithium selectivity in acyclic diamides with bidentate ligands has also been described (Metzger et al., Chimia 1984 38, 440-442; Metzger et al., Anal. Chem. 1986 58, 132-135; Metzger et al., Anal. Chem. 1987 59, 1600-1603); and lithium selectivity in acyclic diamides with quadridentate ligands has been described (Metzger et al., Helvetica Chimica Acta 1986 69, 1821-1828; Metzger et al., Anal. Chem. 1987 59, 1600-1603). Lithium-selective ionophores which are bi-, tri- and quadridentate have also been described (Gadzekpo et al., Anal. Chem. 1986 58, 1948-1953).
In addition, the synthesis of spirodiimides has been disclosed (Adamcik et al., J. Org. Chem., 1963, Vol. 28, 336-339) and the alkylation of 2,5-dioxopyrrolidine has been described (Sury et al., Helv. Chim. Acta 1953 26, 1815-1821). However, these articles disclose only basic synthetic methods and do not suggest the complexing agents of the invention.
A new approach in providing complexing agents with adjustable ion selectivity is highly desirable. An object of the invention is to provide such complexing agents. It is a specific object to provide a new family of compounds which selectively complex with lithium ions relative to sodium and potassium ions and which can be modified to vary selectivity for complexation with other cations. It is yet another object to provide stable complexes of these compounds with ions.